Article

Abnormal surface liquid pH regulation by cultured cystic fibrosis bronchial epithelium.

Cystic Fibrosis/Pulmonary Research and Treatment Center, School of Medicine, University of North Carolina, Chapel Hill, NC 27599-7248, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 01/2004; 100(26):16083-8. DOI: 10.1073/pnas.2634339100
Source: PubMed

ABSTRACT Cystic fibrosis (CF) transmembrane conductance regulator (CFTR)-dependent airway epithelial bicarbonate transport is hypothesized to participate in airway surface liquid pH regulation and contribute to lung defense. We measured pH and ionic composition in apical surface liquid (ASL) on polarized normal (NL) and CF primary bronchial epithelial cell cultures under basal conditions, after cAMP stimulation, and after challenge with luminal acid loads. Under basal conditions, CF epithelia acidified ASL more rapidly than NL epithelia. Two ASL pH regulatory paths that contributed to basal pH were identified in the apical membrane of airway epithelia, and their activities were measured. We detected a ouabain-sensitive (nongastric) H+,K+-ATPase that acidified ASL, but its activity was not different in NL and CF cultures. We also detected the following evidence for a CFTR-dependent HCO3- secretory pathway that was defective in CF: (i). ASL [HCO3-] was higher in NL than CF ASL; (ii). activating CFTR with forskolin/3-isobutyl-1-methylxanthine alkalinized NL ASL but acidified CF ASL; and (iii). NL airway epithelia more rapidly and effectively alkalinized ASL in response to a luminal acid challenge than CF epithelia. We conclude that cultured human CF bronchial epithelial pHASL is abnormally regulated under basal conditions because of absent CFTR-dependent HCO3- secretion and that this defect can lead to an impaired capacity to respond to airway conditions associated with acidification of ASL.

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Available from: Larry G. Johnson, Feb 12, 2015
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    • "First, loss of CFTR impairs HCO 3 – secretion across airway epithelia cultured from humans [4] [5] and pigs with a disrupted CFTR gene [6]; CF pigs spontaneously develop lung disease that mimics human CF [7]. Second, loss of CFTR reduces the pH of airway surface liquid (ASL) in cultured human airway epithelia [5], of secretions from human submucosal glands studied ex vivo [8], and of ASL studied in vivo, ex vivo, and in epithelial cultures from CF pigs [9]. Third, a reduced pH decreases the activity of antimicrobials in ASL in vivo and in vitro, thereby "
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    ABSTRACT: Disrupted HCO3(-) transport and reduced airway surface liquid (ASL) pH in cystic fibrosis (CF) may initiate airway disease. We hypothesized that ASL pH is reduced in neonates with CF. In neonates with and without CF, we measured pH of nasal ASL. We also measured nasal pH in older children and adults. In neonates with CF, nasal ASL (pH5.2±0.3) was more acidic than in non-CF neonates (pH6.4±0.2). In contrast, nasal pH of CF children and adults was similar to values measured in people without CF. At an age when infection, inflammation and airway wall remodeling are minimal, neonates with CF had an acidic nasal ASL compared to babies without CF. The CF:non-CF pH difference disappeared in older individuals, perhaps because secondary manifestations of disease increase ASL pH. These results aid understanding of CF pathogenesis and suggest opportunities for therapeutic intervention and monitoring of disease.
    Journal of cystic fibrosis: official journal of the European Cystic Fibrosis Society 01/2014; 13(4). DOI:10.1016/j.jcf.2013.12.006 · 3.82 Impact Factor
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    • "<15%), removing exogenous CO 2 /HCO 3 − reduces the volume of secretions by ≥50% (Joo et al. 2002). These changes reflect the activity of serous cells in the acini because fluid composition is not altered during transit through the gland (Joo et al. 2006), although some acidification occurs when it reaches the airway surface (Fischer et al. 2002; Coakley et al. 2003). In this paper we studied secretion by Calu-3, a human adenocarcinoma cell line widely used as a model for airway submucosal gland serous cells (Haws et al. 1994). "
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    The Journal of Physiology 07/2012; 590(21). DOI:10.1113/jphysiol.2012.236919 · 4.54 Impact Factor
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    • "Despite much progress, the mechanisms and relationship between anion transport and fluid secretion remain uncertain in Calu-3 cells and in gland serous cells. HCO 3 − appears to be the only actively secreted anion under I sc conditions, consistent with bumetanide-insensitive fluid secretion by native airway glands (Corrales et al. 1984), yet most studies indicate that the pH of native gland secretions and airway surface liquid is near neutrality or slightly acidic (Kyle et al. 1990; Coakley et al. 2003; Song et al. 2006; reviewed by Fischer & Widdicombe, 2006). "
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    The Journal of Physiology 07/2012; 590(21). DOI:10.1113/jphysiol.2012.236893 · 4.54 Impact Factor
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